The continuous dissolution and oxidation of active sites in Ru-based electrocatalysts have greatly hindered their practical application in proton exchange membrane water electrolyzers (PEMWE). In this work, we first used density functional theory (DFT) to calculate the dissolution energy of Ru in the 3d transition metal-doped MRuO x (M = Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, and Zn) to evaluate their stability for acidic oxygen evolution reaction (OER) and screen out ZnRuO x as the best candidate. To confirm the theoretical predictions, we experimentally synthesized these MRuO x materials and found that ZnRuO x indeed displays robust acidic OER stability with a negligible decay of η 10 after 15 000 CV cycles. Of importance, using ZnRuO x as the anode, the PEMWE can run stably for 120 h at 200 mA cm −2 . We also further uncover the stability mechanism of ZnRuO x , i.e., Zn atoms doped in the outside of ZnRuO x nanocrystal would form a "Zn-rich" shell, which effectively shortened average Ru−O bond lengths in ZnRuO x to strengthen the Ru−O interaction and therefore boosted intrinsic stability of ZnRuO x in acidic OER. In short, this work not only provides a new study paradigm of using DFT calculations to guide the experimental synthesis but also offers a proof-of-concept with 3d metal dopants as RuO 2 stabilizer as a universal principle to develop high-durability Ru-based catalysts for PEMWE.